Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of salmon calcitonin and human calcitonin on the fluorescence spectra of a fluorescent conjugate of calmodulin with dansyl-chloride and on the calmodulin mediated activation of phosphodiesterase have been studied. We showed that salmon calcitonin provoked calcium-dependent modifications of the spectra of dansyl-calmodulin and completely inhibited the calmodulin mediated activation of phosphodiesterase with a maximum effect at the dose of 5.8 X 10(-7)M and 10(-7) M respectively. No appreciable effect of human calcitonin was observed in either system. This interaction of salmon calcitonin with calmodulin is similar to the interaction of certain neuropeptides and antipsychotic drugs to calmodulin and may explain certain of the peptide's pharmacological effects.
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PMID:In vitro interaction between calcitonin and calmodulin. 632 57

We investigated the relaxant mechanisms of calcitonin gene-related peptide (CGRP) in endothelium-denuded porcine coronary arteries. Intracellular free calcium concentration ([Ca++]i) was measured simultaneously with force by the fura-2 microfluorimetric method. CGRP (10(-9) to 10(-7) M) or isoproterenol (10(-8) to 10(-5) M) produced a concentration-dependent relaxation of arterial rings precontracted with 30 mM KCl with only a slight decrease in [Ca++]i. In contrast, cromakalim (3 x 10(-7) to 3 x 10(-5) M), an ATP-sensitive potassium channel opener, reduced [Ca++]i and force in a parallel manner. When the arteries were precontracted with 90 mM KCl, the relaxant effects of CGRP and isoproterenol were attenuated, whereas that of cromakalim was abolished. In arteries precontracted with 90 mM KCl, reduction of extracellular calcium concentrations from 2.5 to 0.1 mM recovered the relaxant effects of CGRP and isoproterenol, but not that of cromakalim. All three relaxants reduced both [Ca++]i and force in arteries precontracted with endothelin-1 (10(-8) M). Glibenclamide (10(-5) M) inhibited the decrease in [Ca++]i and the relaxation caused by cromakalim, but had virtually no effect on those produced by CGRP or isoproterenol. In arteries precontracted with 30 mM KCl and relaxed maximally by isoproterenol (10(-5) M), CGRP (10(-7) M) failed to produce any relaxant effect, whereas cromakalim (10(-5) M) reduced [Ca++]i and force further. The inhibitor of phosphodiesterase, 3-isobutyl-1-methylxanthine, potentiated the decreases in [Ca++]i and relaxations caused by CGRP and isoproterenol, but not those by cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcitonin gene-related peptide relaxes porcine coronary arteries via cyclic AMP-dependent mechanisms, but not activation of ATP-sensitive potassium channels. 768 42

Mouse mesenteric lymph node cells were incubated with concanavalin A (Con A) with or without the rat form of calcitonin gene-related peptide (rCGRP) (0.1 fM-1 microM) +/- human (h)CGRP8-37 (1 microM) for 48 h. DNA synthesis was assessed by [3H]thymidine incorporation. Con A-stimulated DNA synthesis was suppressed by 13, 20, and 30% at 10 fM, 1 pM, and 100 pM of rCGRP, respectively. hCGRP8-37 (1 microM), a selective blocker of CGRP1 receptor, completely inhibited the suppression of DNA synthesis by rCGRP (10 fM-100 pM). rCGRP caused concentration-dependent elevations of cAMP levels, which were potentiated by pretreatment with 3-isobutyl-1-methylxanthine (0.3 mM, 10 min), an inhibitor of cAMP-phosphodiesterase. hCGRP8-37 (1 microM) significantly inhibited cAMP elevations induced by rCGRP at the lower concentrations, but not at the highest concentrations of rCGRP. These data suggest that rCGRP, at circulating levels (1-10 pM), appears to directly interact with receptors on mouse mesenteric lymph node cells that are coupled to cAMP generation, ultimately inhibiting lymphocyte proliferation. To test the involvement of CGRP in suppression of lymphocyte proliferation by serum from endotoxin-treated rats, mouse mesenteric lymph node cells were stimulated with Con A with or without dilutions of endotoxin treated rat serum. At a 1:20 dilution, DNA synthesis was suppressed 30%, at a 1:40 dilution, DNA synthesis was suppressed by 34%, and at a 1:80 dilution, DNA synthesis was suppressed 25%. At all serum dilutions, coincubation with hCGRP8-37 (1 microM) significantly inhibited the suppressive effect of the endotoxin treated rat serum. These data suggest that the immunosuppression observed during endotoxin shock may be due, at least in part, to CGRP in serum.
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PMID:CGRP in the serum of endotoxin-treated rats suppresses lymphoproliferation. 769 15

CGRP is a 37-amino acid neuropeptide found in the central and peripheral nervous systems as well as the nerve endings in lymphoid organs. Specific CGRP receptors are present on both T and B lymphocytes. There is increasing evidence that CGRP plays a role in regulation of the immune response. However, few investigations have examined the effects of CGRP on lymphocyte effector functions. In this report, CGRP (0.1 nM-1 microM) was shown to cause concentration-dependent inhibition of IL-2-activated lymphocyte growth inhibition of the fungus Candida albicans and cytotoxic activity for tumor cells. Maximum inhibition of lymphocyte activity by CGRP was 47.4% for the hyphae of C. albicans, 44.8% for a natural killer cell susceptible cell line, and 52.9% for a natural killer cell-resistant cell line. CGRP-mediated inhibition of lymphocyte function was mimicked by 8-bromo-cAMP (1 mM) and was correlated in a concentration-dependent manner with an increase in intracellular levels of cAMP. These increases were potentiated by pretreatment of the lymphocytes with 3-isobutyl-1-methylxanthine (0.5 mM, 10 min), an inhibitor of the cAMP phosphodiesterase. hCGRP 8-37, a selective blocker of the CGRP1 receptor, abrogated the effect of CGRP on lymphocyte function and on intracellular cAMP level elevation induced by rCGRP. CGRP had no direct effect on the capacity of IL-2-activated lymphocytes to adhere to the hyphae of C. albicans. However, both CGRP and 8-bromo-cAMP diminished the capacity of the lymphocytes to release cytoplasmic granular content when stimulated by the hyphae of C. albicans. These data show that CGRP inhibits functional activity of IL-2-activated lymphocytes and suggest that hCGRP8-37 may be a useful tool for assessing the role of CGRP in the immune system.
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PMID:Suppression of the functional activity of IL-2-activated lymphocytes by CGRP. 770 98

Rat calcitonin gene-related peptide (rCGRP) causes endothelium-dependent vasorelaxations via a dual signal transduction mechanism involving elevations of both cyclic AMP and cyclic GMP levels in rat aorta. These responses are all dependent on de novo synthesis of nitric oxide (NO) in endothelial cells and appear to involve a mechanistic link between cyclic GMP and cyclic AMP responses in smooth muscle cells. The present study determined whether NO from an exogenous source (i.e. added nitroglycerin) could substitute for endogenous NO in rCGRP-induced responses in endothelium-denuded aorta. Nitroglycerin (1 microM) significantly elevated cyclic GMP levels by 20-fold and 3.3-fold and cyclic AMP levels by 26% and 22% at 1 and 2 min, respectively. By itself, rCGRP (100 nM) did not significantly elevate cyclic AMP levels. In combination, however, nitroglycerin and rCGRP caused more-than-additive cyclic AMP elevations (41% above basal at 1 and 2 min). Nitroglycerin also potentiated rCGRP-induced vasorelaxations in endothelium-denuded rings, thus uncovering a direct (endothelium-independent) relaxant effect of rCGRP in rat aorta. The data indicate that exogenous NO can substitute for endogenous NO in rCGRP-induced relaxant and cyclic AMP responses in aorta. This nitroglycerin-induced potentiation of CGRP effects likely involves inhibition of cyclic-GMP-inhibited-phosphodiesterase in smooth muscle cells, thus allowing cyclic AMP to accumulate and mediate the direct vasodilator effects of rCGRP.
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PMID:Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta. 817 May 22

1. The aim of this study was to assess whether agents that interfere with the intracellular actions of cAMP and activation of protein kinase A (PKA) prevent the inhibitory action of human alpha-calcitonin gene-related peptide (CGRP) in the guinea-pig ureter smooth muscle. The action of CGRP was compared to that of the K+ channel opener, cromakalim, and the adenylyl cyclase activator, forskolin, toward electrical field stimulation- (EFS) induced myogenic twitch contractions of the ureter. To further verify the role of cAMP in the action of CGRP, we also studied the effect of stable cAMP analogues and of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). 2. Maximally effective concentrations of CGRP (0.1 microM) or forskolin (10 microM) produced a transient suppression of twitches. Cromakalim (3 microM) likewise produced a prompt suppression of twitches that in most cases exceeded 15 min. The early suppressant effect of CGRP or forskolin was inhibited by 1 or 10 microM glibenclamide; about 30% of the effect of CGRP was glibenclamide-resistant. The effect of cromakalim was totally suppressed by glibenclamide. 3. The inhibitory effect of CGRP was concentration-dependently reduced by low concentrations of barium chloride (IC50 63 microM), which blocked with similar potency the inhibitory action of cromakalim (IC50 60 microM). Glibenclamide (10 nM-10 microM) concentration-dependently inhibited the effect of CGRP and cromakalim with IC50S of 0.13 and 0.72 microM, respectively. 4. The cAMP analogues dibutyrye-cAMP (1-3 mM), 8-(4-chlorophenylthio)cAMP (0.3-1 mM) and Sp-cAMP monophosphothioate (0.1-0.3 mM) were either ineffective or poorly effective in inhibiting twitches. The cGMP analog, 8Br-cGMP (100-300 microM) produced a slowly developing, glibenclamide (1 microM)-resistant partial inhibition (25-30%) of twitches. 5. IBMX (1-300 microM) produced a concentration-dependent inhibition of twitches (EC50 16 microM). IBMX (100 microM) produced a large (peak 91%) and transient inhibition: glibenclamide (1 microM) blocked the early peak of the inhibitory action of IBMX, similar to the effect observed toward CGRP and forskolin.
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PMID:Role of cyclic AMP and protein kinase A in K+ channel activation by calcitonin gene-related peptide (CGRP) in the guinea-pig ureter. 874 80

Previously, men with erectile dysfunction (ED) were frequently treated with penile prosthesis implants or considered to have psychogenic impotence. Since the reports by Virag and Brindley in 1932 and 1983, pharmacotherapy, by self-injection programs has become a new therapeutic concept for impotent men. In clinical practice, this application model has been generally accepted as the "golden standard" in the treatment of ED. Papaverine was first used as monotherapy, but because of side-effects such as prolonged erection, priapism, and fibrosis of the corpus cavernosum, single use of the drug was abandoned. Instead, papaverine was introduced in mixtures, e.g. together with alpha adrenoceptor-blockers as phentolamine, and/or prostaglandin E1 (PGE1) in these "cocktails", the dose of papaverine is reduced to 10-15 mg compared to the high doses (80-120 mg) that were used initially. By having two or more drugs in the mixture, a facilitating cascade effect as probably obtained. PGE1 is the only drug that has been approved by the FDA and is today registered in more than 50 countries. Other combination therapies such as vasoactive intestinal polypeptide+ phentolamine, or calcitonin gene-related peptide+ PGE1, have been suggested as suitable alternatives for intracavernosal injection. Transdermal and intraurethral application models may be considered in selected patients. Recently, oral administration of a phosphodiesterase inhibitor (UK-92.480) was reported to improve penile erection in patients with psychogenic impotence. Further clinical results from controlled trials will probably explain if this new oral drug will compete with PGE1 or other agents in self-injection programs.
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PMID:Pharmacotherapy in erectile dysfunction agents for self-injection programs and alternative application models. 890 79

The effects of adrenomedullin (ADM)-(22-52), a putative ADM receptor antagonist, on vasodilator responses to ADM and the structurally related peptide, calcitonin gene-related peptide (CGRP), were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. ADM-(22-52) had no significant effect on hindlimb perfusion pressure when injected in doses up to 120 nmol; after administration of ADM-(22-52), vasodilator responses to ADM were unchanged, whereas vasodilator responses to CGRP were inhibited. The inhibitory effects of ADM-(22-52) on responses to CGRP were selective and reversible and were similar to the inhibitory effects of the CGRP antagonist CGRP-(8-37). Hindlimb vasodilator responses to CGRP and to ADM were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor rolipram but were not altered by inhibitors of guanosine 3',5'-cyclic monophosphate phosphodiesterase, nitric oxide synthetase, K(+)-ATP channels, the cyclooxygenase pathway, or the adrenergic nervous system. These results demonstrate that ADM-(22-52) is a selective CGRP receptor antagonist in the hindlimb vascular bed of the cat. The present data suggest that vasodilator responses to CGRP and ADM are mediated by different receptors but that these peptides dilate the hindlimb vascular bed of the cat by a similar cAMP-dependent mechanism.
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PMID:Adrenomedullin-(22-52) antagonizes vasodilator responses to CGRP but not adrenomedullin in the cat. 903 14

The mechanism by which proadrenomedullin NH2-terminal 20 peptide (PAMP) decreases vascular resistance was investigated in the hindlimb vascular bed in the cat. Injections of PAMP, a shortened form of the peptide PAMP-(12-20), and adrenomedullin (ADM) into the hindlimb perfusion circuit elicit dose-related decreases in perfusion pressure. The order of potency was ADM > PAMP > PAMP-(12-20), and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) had no effect on vasodilator responses to PAMP or ADM. Vasodilator responses to PAMP were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor Rolipram, whereas inhibitors of nitric oxide synthase and guanosine 3',5'-cyclic monophosphate phosphodiesterase had no effect. Vasodilator responses to PAMP were not altered by treatment with alpha-receptor or adrenergic nerve terminal blocking agents and were similar in innervated and denervated hindlimb preparations. Responses to PAMP were similar when vasoconstrictor tone was increased by stimulation of the sympathetic nerves or infusion of phenylephrine and were not altered by the passage of time. These data suggest that PAMP dilates the hindlimb vascular bed by a direct cAMP-dependent mechanism and that inhibition of norepinephrine release plays little if any role in mediating responses to the peptide in the regional vascular bed of the cat.
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PMID:Proadrenomedullin NH2-terminal 20 peptide has direct vasodilator activity in the cat. 914

Responses to rat (r) adrenomedullin (ADM) and human (h) ADM were compared in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intra-arterial injections of rADM and hADM in doses of 0.03-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, rADM was similar to hADM. The time course of the vasodilator response and the recovery half times (T1/2) for the vasodilator response to rADM and hADM were not significantly different. Decreases in hindlimb perfusion pressure in response to rADM and hADM were not altered by the calcitonin gene-related peptide receptor antagonist, rCGRP(8-37), at the same time, vasodilator responses to calcitonin gene-related peptide (CGRP) were significantly reduced. The T1/2 of the vasodilator response to rADM and hADM were significantly greater after administration of the cAMP-selective, type IV phosphodiesterase inhibitor, rolipram. These data demonstrate that decreases in hindlimb perfusion pressure in response to rADM and hADM are similar and that vasodilator responses to rADM are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. These data further suggest that decreases in hindlimb perfusion pressure in response to rADM are mediated by smooth muscle increases in cAMP levels.
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PMID:Comparison of responses to rat and human adrenomedullin in the hindlimb vascular bed of the cat. 927 28


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